University of Arizona neuroscientists have come up with a new treatment approach for PPA that combines traditional speech therapy with noninvasive electrical stimulation of the brain. The technique — called transcranial direct current stimulation — uses a low electrical current applied through electrodes on the scalp.

A new study published in the Journal of Speech, Language, and Hearing Research describes the treatment approach, which the researchers found to be more effective at managing PPA compared to speech therapy alone.

“Primary progressive aphasia is a condition that causes worsening of communication skills over time. It was identified in the literature only in the last three to four decades, so it is considered pretty new in the health care world — it’s still an understudied area,” said Katlyn Nickels, the study’s lead researcher and a postdoctoral researcher in the U of A Department of Speech, Language and Hearing Sciences.

While writing and speaking words, people don’t just retrieve their meaning. They also retrieve the sound of a word while it is being spoken or written, said Aneta Kielar, the study’s senior author and an associate professor in the Department of Speech, Language and Hearing Sciences.

If there is a problem with associating words with the way they sound, it is difficult to put letters together and speak or write a word, Kielar said. This affects people’s communication in their day-to-day life and their ability to work. For their study, the researchers focused on a type of PPA called the logopenic PPA, in which people have trouble finding the right words and repeating phrases or sentences.

The researchers did neuroimaging analysis of the brain to determine the area of the brain that needs to be stimulated, as people with PPA have brain atrophy or a loss of brain cells.

“We wanted to stimulate the area that is most responsive to language and were careful not to stimulate an area that would have been atrophied already,” Kielar said.

Twelve individuals with written language deficits each received two phases of treatment: in one phase, they got speech therapy paired with active transcranial direct current stimulation. In another phase, they received the same speech therapy with placebo transcranial direct current stimulation. The order of the phases was randomized and separated by a two-month break in between.

Although all participants improved after both treatments, they showed greater and more lasting improvement following the phase with active transcranial direct current stimulation compared to placebo transcranial direct current stimulation.

“People who made numerous spelling errors and struggled to frame complete sentences before the treatment were able to form sentences that were grammatically correct, had fewer spelling errors and were more meaningful after treatment,” Kielar said.

The researchers say brain stimulation helped induce neuroplasticity, the brain’s capacity to continue to reorganize and learn. And it boosted the effects of speech therapy.

“What that means is that brain stimulation can induce the formation of synapses, the connections between neurons. These connections are important for people’s ability to learn and maintain new skills,” Kielar said.

In the future, the research group is planning to look at the genetic, cognitive and neural markers that influence the recovery from PPA. The researchers’ long-term goal is to translate their research findings to a clinical setting.

Because transcranial direct current stimulation is inexpensive, safe and easy to perform, the barriers to implementing it in clinical practice are less significant, Nickels said.

“There’s a misconception sometimes with neurodegenerative diseases, that once you get a diagnosis, there is nothing that can be done,” Nickels said. “But we have learned through our research that even when there’s a progressive brain disease, we can help restore lost function and even slow down the progression.”

This work was supported by the following grants to the senior author, Aneta Kielar: Arizona Alzheimer’s Consortium Grant, Arizona Department of Health Services (018676-00001); Innovations in Healthy Aging: Grand Challenges of Aging Seed Grant, The University of Arizona Health Sciences (2259304); and Data Science Academy-Transdisciplinary Research in Principles of Data Science at The University of Arizona (2259910). Research reported in the publication was supported by the Arizona Department of Health Services and the state of Arizona (ADHS Grant No. CTR057001) to Aneta Kielar.

Proteins and protein coding genes increase in length

The article in PNAS demonstrates that the distributions of protein lengths and their corresponding genes follow log-normal distributions across the whole tree of life. To do this, 9,913 different proteomes and 33,627 genomes were analyzed. Log-normal distributions typically arise as a result of multiplicative processes. Following Ockham’s razor principle, the researchers modeled the evolution of gene length distributions as multiplicative stochastic processes. In fact, they modeled the action of all genetic operators combined in relation to sequence length. Starting from LUCA, i.e., the hypothesized last universal common ancestor from which the three domains of life — the Bacteria, the Archaea, and the Eukarya — originated, the researchers found both theoretically and observationally that the average gene lengths have evolved exponentially over evolutionary time across different species. Furthermore, they discovered a scaling-invariant mechanism of gene growth across the entire tree of life, where the variance directly depends on the mean protein length. By representing all the species captured in the 33,627 genomes, the team was able to observationally verify the predictions and, moreover, show that the average gene length is a very good surrogate for organismal complexity. In a pure exercise of quantitative biology, Dr. Bartolo Luque from the Polytechnic University of Madrid added: “From knowing the average length of protein-coding genes in a species, we can calculate the whole distribution of gene length within that species.”

When representing the evolution of the average protein lengths versus their corresponding gene lengths across different species, it is observed that they evolve simultaneously in prokaryotes, because there are almost no non-coding sequences in their genes. However, once the average gene length reaches 1,500 nucleotides, the proteins decouple from the multiplicative process of gene growth, and the average protein length stabilizes after the onset of the eukaryotic cell at about 500 amino acids in a clear threshold, marking the appearance of the eukaryotic cell. From that point onward, and unlike what happens with proteins, the average gene length continues to increase as it did in prokaryotes, due to the presence of non-coding sequences.

Algorithmic phase transition

A critical phenomena analysis then concluded that a phase transition, well studied in the physics of magnetic materials, occurred at a critical gene length of 1,500 nucleotides. This marked eukaryogenesis and divides the evolution of life into two distinct phases: a coding phase (Prokarya) and a non-coding phase (Eukarya). Additionally, characteristic phenomena of these transitions are observed, such as critical slowing down, where the system’s dynamics become trapped in many metastable states around the critical point. “This is corroborated in early protists and fungi,” said Dr. Fernando Ballesteros from the University of Valencia.

Moreover, “the phase transition was algorithmic,” added Professor Jordi Bascompte from the University of Zurich. In the coding phase, in a scenario close to LUCA, with short proteins, increasing the length of proteins and their corresponding genes was computationally simple. However, as the protein lengths grew, the search for longer proteins became unfeasible. This tension caused by genes that grew at the same rate as before while proteins could not was resolved continuously but abruptly with the incorporation of non-coding sequences into the genes. With this innovation, the algorithm for searching for new proteins rapidly reduced its computational complexity, becoming non-linear through the spliceosome and the nucleus, which separated transcription and splicing from translation. This happened at the critical point of phase transition, which this study dates to 2.6 billion years ago.

The study recently published in PNAS not only answers essential questions, but is interdisciplinary, combining computational biology, evolutionary biology, and physics. “It has the potential to interest a wide audience across many disciplines and serve as a foundation for other groups to explore different research avenues, such as energy or information theory,” emphasized Dr. Enrique Muro of the Institute of Organismic and Molecular Evolution at Mainz University. The eukaryotic cell, the most significant increase in complexity in the history of life’s evolution on Earth, emerged as a phase transition and unlocked the path toward other major transitions — such as multicellularity, sexuality, and sociability — that shaped life on our planet as we know it today.

Published on Friday in the International Journal of Obesity, the research is the first to test in humans the relationship between HFHS diets, particularly those high in refined sugar and saturated fat, and first-person spatial navigation. Spatial navigation is the ability to learn and remember a path from one location to another, a process that can approximate the health of the brain’s hippocampus.

Dr Dominic Tran from the Faculty of Science’s School of Psychology led the research, which found HFHS diets have a detrimental effect on some aspects of cognitive function. It is likely those effects centre on the hippocampus, the brain structure important for spatial navigation and memory formation, rather than acting across the entire brain.

“The good news is we think this is an easily reversible situation,” Dr Tran said. “Dietary changes can improve the health of the hippocampus, and therefore our ability to navigate our environment, such as when we’re exploring a new city or learning a new route home.”

The research team recruited 55 university students aged between 18 and 38. Each participant completed questionnaires capturing their intake of sugary and fatty foods. They also had their working memory tested in a number recall exercise, and their body mass index (BMI) recorded.

The experiment itself required participants to navigate a virtual reality maze and locate a treasure chest six times. The maze was surrounded by landmarks that participants could use to remember their route. Their starting point and the location of the treasure chest remained constant in each trial.

If participants found the treasure in less than four minutes, they continued to the next trial. If they failed to find the treasure in this time, they were teleported to its location and given 10 seconds to familiarise themselves with that location before the next trial.

A seventh trial removed the treasure chest from the virtual maze but asked participants to find and mark its former location based purely on memory. Those with lower levels of fat and sugar in their diets were able to pinpoint the location with a higher degree of accuracy than those who consumed these foods multiple times a week.

“After controlling for working memory and BMI, measured separately to the experiment, participants’ sugar and fat intake was a reliable predictor of performance in that final, seventh, test,” Dr Tran said.

Dr Tran said the results highlight the importance of making good dietary choices to maintain healthy brain function.

“We’ve long known eating too much refined sugar and saturated fat brings the risk of obesity, metabolic and cardiovascular disease, and certain cancers. We also know these unhealthy eating habits hasten the onset of age-related cognitive decline in middle age and older adults.

“This research gives us evidence that diet is important for brain health in early adulthood, a period when cognitive function is usually intact,” Dr Tran said.

Dr Tran said the sample group used in this research was not representative of the wider population, but the findings still apply more broadly.

“It’s likely our participants were a little healthier than the general population and we think, if our sample better represented the public, the impact of diet on spatial navigation would likely be even more pronounced.”

Dr Tran is a recipient of an Australian Research Council Discovery Early Career Research Award (DECRA).